Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the United States and is currently incurable. New tyrosine kinase inhibitors such as ibrutinib (BTK inhibitor) have shown very strong clinical responses. Despite this, they do not eradicate the malignant clone and resistance has emerged. Thus, combination strategies that target BTK are a high priority. Chromosome Region Maintenance 1 (CRM1/XPO1) is a nuclear export protein that shuttles tumor suppressor proteins such p53, I?B, and FoxO3a out of the nucleus, thereby preventing their anti-apoptotic and anti-proliferative function. XPO1 is overexpressed in many different solid and hematopoietic malignancies and is associated with poor prognosis and resistance to treatment. Our group has shown that inhibition of XPO1 by selective inhibitors of nuclear export (SINEs) is a promising therapeutic strategy in preclinical models of CLL and responses have been observed in ongoing clinical trials. Interestingly, XPO1 is recurrently mutated in CLL patients at a highly conserved residue in the cargo binding pocket. The function of this mutation remains unknown. We propose to determine the function of mutant and wild-type XPO1 and its role in CLL pathogenesis. Our aims are 1) to determine the ability of mutant XPO1 to bind to target proteins and RNAs compared to wild-type, thereby establishing the functional significance of this disease associated mutation and 2) to overexpress mutant and wild-type XPO1 in a B cell specific manner in normal and leukemic mice, which will determine its role in leukemogenesis and CLL disease progression. Finally, we will 3) evaluate the dual inhibition of XPO1 and BTK (ibrutinib) as a relevant therapeutic strategy in CLL. Our long-term goals are to improve targeted therapies for CLL patients and to elucidate fundamental aspects of XPO1 biology that will have relevance to many other cancers.